N-substituted azabicycloheptane derivatives, production and use thereof

ABSTRACT

Compounds of the formula I:                    
     in which R 1 , R 2 , R 3  and R 4  have the meanings stated in the description, are described. 
     The novel compounds are suitable for controlling diseases.

This application is a 371 of PCT/EP99/05164 filed Jul. 20, 1999.

The invention relates to novel N-substituted azabicycloheptanederivatives, their preparation and use for controlling diseases.Exo-6-phenyl-3-azabicyclo[3.2.0]heptane derivatives have interestingproperties as potential neuroleptics (WO 94/00458, WO 95/15312). In thisconnection, the observed high affinities for D₄ and 5-HT₂ receptors areparticularly important.

The most interesting substance from the above classes of compounds withhigh D₄/5-HT_(2A) affinity and good selectivity versus D₂ is(+)-(1S,5R,6S)-exo-3-[2-[6-(4-fluorophenyl)-3-azabicyclo-[3.2.0]heptan-3-yl]ethyl]-1H,3H-quinazoline-2,4-dione(=substance A), which represents a potential neuroleptic. However, thereis an upper limit to the dosage of substance A owing to theprolongations occurring in the QT interval in the cardiac [sic] ECG.

Substances with better properties have now been found.

The invention relates to N-substituted 3-azabicyclo-[3.2.0]heptanederivatives of the formula I:

in which

R¹ is fluorine or chlorine,

R² and R³ are hydrogen or C₁-C₃-alkyl, and

R⁴ is chlorine, methyl, nitro or amino,

and the salts thereof with physiologically tolerated acids.

Preferred compounds are those in which

R¹ is chlorine, preferably in the p position,

R² is hydrogen or methyl,

R³ is hydrogen or methyl and

R⁴ is hydrogen.

The following compounds should be mentioned as particularly preferred:

(+)-(1S,5R,6S)-exo-2-[2-[6-(4-chlorophenyl)-3-azabicyclo-[3.2.0]heptan-3-yl]ethyl]-3,3-dimethyl-2,3-dihydro-1,2-benzisothiazole1, 1-dioxide,

(+)-(1S,5R,6S)-exo-2-[2-[6-(4-chlorophenyl)-3-azabicyclo-[3.2.0]heptan-3-yl]ethyl]-2,3-dihydro-1,2-benzisothiazole1,1-dioxide, and

(+)-(1S,5R,6S)-exo-2-[2-[6-(4-fluorophenyl)-3-azabicyclo-[3.2.0]-heptan-3-yl]-ethyl]-2,3-dihydro-1,2-benzisothiazole-1,1-dioxide.

The compounds of the formula I according to the invention can beprepared by reacting a compound of the formula II:

in which R², R³ and R⁴ have the abovementioned meanings, and Nu is anucleofugic leaving group, with a 3-azabicyclo-[3.2.0]heptane derivativeof the formula III as (+)-(1S,5R,exo-6S) enantiomer:

in which R¹ has the abovementioned meaning, and converting the compoundobtained in this way where appropriate into the acid addition salt of aphysiologically tolerated acid.

Halogen atoms, in particular bromine or chlorine, are suitable andpreferred as nucleofugic leaving group for Nu.

The reaction is expediently carried out in the presence of an inert basesuch as triethylamine or potassium carbonate as acid acceptor in aninert solvent such as a cyclic saturated ether, in particulartetrahydrofuran or dioxane, or a benzenoid hydrocarbon such as tolueneor xylene.

The reaction is generally carried out at temperatures from 20 to 150°C., in particular from 80 to 1400C., and is generally complete within 1to 10 hours.

The compounds of the formula I according to the invention can be eitherrecrystallized by recrystallization [sic] from conventional organicsolvents, preferably from a lower alcohol such as ethanol, or purifiedby column chromatography.

The free 3-azabicyclo[3.2.0]heptane derivatives of the formula I can beconverted in a conventional way into the acid addition salt of apharmacologically suitable acid, preferably by treating a solution withone equivalent of the appropriate acid. Examples of pharmaceuticallysuitable acids are hydrochloric acid, phosphoric acid, sulfuric acid,methanesulfonic acid, sulfamic acid, maleic acid, fumaric acid, oxalicacid, tartaric acid or citric acid.

The compounds according to the invention have valuable pharmacologicalproperties. They can be used as neuroleptics (in particular atypical),antidepressants, sedatives, hypnotics, CNS protectives or agents fortreating cocaine dependency. It is possible for several of the types ofaction mentioned to occur in combination in a compound according to theinvention.

The substances are characterized in particular by a very high andselective affinity for dopamine D₄ and serotonin 2A receptors.

The prolongations of the QT interval measured on the model of the guineapig capillary muscle are negligibly small. The novel substances aretherefore well tolerated even at high dosages.

The invention accordingly also relates to a therapeutic compositionhaving a content of a compound of the formula I or its pharmacologicallysuitable acid addition salt as active ingredient in addition toconventional carriers and diluents, and to the use of the novelcompounds for controlling diseases.

The compounds according to the invention can be administered orally orparenterally, intravenously or intramuscularly, in a conventional way.

The dosage depends on the age, condition and weight of the patient andon the mode of administration. As a rule, the daily dose of activeingredient is between about 1 and 100 mg/kg of body weight on oraladministration and between 0.1 and 10 mg/kg of body weight on parenteraladministration.

The novel compounds can be used in conventional solid or liquidpharmaceutical forms, e.g. as uncoated or (film-)coated tablets,capsules, powders, granules, suppositories, solutions, ointments, creamsor sprays. These are produced in a conventional way. The activeingredients can for this purpose be processed with conventionalpharmaceutical aids such as tablet binders, bulking agents,preservatives, tablet disintegrants, flow regulators, plasticizers,wetting agents, dispersants, emulsifiers, solvents, release-slowingagents, antioxidants and/or propellant gases (cf. H. Sucker et. al.:Pharmazeutische Technologie, Thieme-Verlag, Stuttgart, 1978). Theadministration forms obtained in this way normally contain the activeingredient in an amount of from 1 to 99% by weight.

The substances of the formula II and III required as starting materialsfor synthesizing the compounds according to the invention are known, (WO94/00458; Heterocycles 40 (1), 319-330 (1995), Chimia 1990, 44, 120) orcan be synthesized from analogous starting materials by preparationmethods described in the literature.

The following examples serve to illustrate the invention:

A Preparation of the Starting Materials

a) 2,3-dihydro-1,2-benzoisothiazole 1,1-dioxide

25.3 g (138 mM [sic]) of saccharin were added in portions over thecourse of 90 min to 7.1 g (187 mM [sic]) of lithium aluminum hydride in400 ml of absolute tetrahydrofuran with vigorous stirring undernitrogen; during this, the temperature was maintained at roomtemperature by cooling in ice. After stirring overnight, the mixture wascooled in an ice bath and, while stirring vigorously, water wascautiously added dropwise, followed by 10% strength sulfuric acid. Afterthe precipitated hydroxides had been filtered off with suction, washingwith THF, the filtrate was concentrated, the residue was partitionedbetween methylene chloride and water and, after acidifying with 10%strength sulfuric acid, the organic phase was washed thoroughly withsodium carbonate solution. The organic phase was dried with sodiumsulfate and filtered and then concentrated. 12.0 g (52%) of product ofadequate purity were isolated.

b) 3,3-Dimethyl-2,3-dihydro-1,2-benzoisothiazole 1,1-dioxide wasprepared in a manner known from the literature (K.

Auer, E. Hungerbuhler, R. W. Lang Chimia 1990, 44, 120).3,3-Diethyl-2,3-dihydro-1,2-benzoisothiazole 1,1-dioxide (m.p.: 174°C.), 3,3-dimethyl-6-nitro-2,3-dihydro-1,2-ben-zoisothiazole 1,1-dioxide(m.p.: 1870) and 3,3-dime-thyl-4-chloro-2,3-dihydro-1,2-benzisothiazole1,1-dioxide were obtained analogously.

c) 2-(2-Chloroethyl)-3,3-dimethyl-2, 3-dihydro-1,2-benzoiso-thiazole1,1-dioxide

2.1 g (32 mM [sic]) of 88% KOH powder and 250 mg ofbenzyltriethylammonium chloride were added to 2.5 g (12.7 mM [sic]) of3,3-dimethyl-2,3-dihydro-1, 2-benzoisothiazole 1,1-dioxide in 50 ml of1,2-dichloroethane, and the mixture was refluxed for 1 h. After cooling,the mixture was partitioned between ice-water and methylene chlorideand, after making weakly acidic with hydrochloric acid, the organicphase was separated off. After the organic phase had been dried withsodium sulfate and concentrated, 3.2 g (97%) of product were isolated asan oil of adequate purity.

2-(2-Chloroethyl)-3,3-dimethyl-6-nitro-2,3-dihydro-1, 2-benzoisothiazole1,1-dioxide, 2-(2-chloroethyl)-3,3-diethyl-2,3-dihydro-1,2-benzoisothiazole 1,1-dioxide and2-(2-chloroethyl)-4-chloro-3,3-dimethyl-2,3-dihydro-1,2-benzoisothiazole 1,1-dioxide can be prepared in an analogous manner.

d) (+)-(1S,5R,6S)-Exo-6-(4-chlorophenyl)-3-azabicyclo-[3.2.0]heptane

The (+)-enantiomer was isolated by the method in Heterocycles 40 (1),326 (1995).

e) (+)-(1S,5R,6S)-Exo-[3-(2-chloro)ethyl]-6-(4-chloro-phenyl)-3-azabicyclo[3.2.0]heptane [sic]

7.3 g (50 mM [sic]) of 1-bromo-2-chloroethane and 3.5 g (25 mM [sic]) offinely powdered potassium carbonate were added to 10.0 g (48.2 mM [sic])of (+)-(1S,5R,6S)-exo-6-(4-chlorophenyl)-3-azabicyclo[3.2.0]heptane in200 ml of tetrahydrofuran, and the mixture was refluxed for 15 h. Themixture was then concentrated in a rotary evaporator, and the residuewas taken up in 200 ml of methyl tert-butyl ether. The organic phase waswashed with water at pH 10 and then the aqueous phase was back-extractedwith methyl tert-butyl ether. The combined organic phases were driedwith sodium sulfate and then concentrated. The crude product waspurified by flash chromatography (silica gel, mobile phase ethylacetate/n-heptane 1/1). 6.7 g (52%) of product were isolated as an oilwith [α]_(D)=+91.70 (EtOH).

(+)-(1S,5R,6S)-Exo-[3-(2-chloro)ethyl]-6-(4-fluorophenyl)-3-azabicyclo[3.2.0]heptane [sic] was prepared in ananalogous manner.

B Preparation of the Final Products

EXAMPLE 1 (+)-(1S,5R,6S)-Exo-2-[2-[6-(4-chlorophenyl)-3-azabicyclo-[3.2.0]heptan-3-yl]ethyl]-3,3-dimethyl-2,3-dihydro-1,2-benzoisothiazole 1,1-dioxide×HCl

3.75 g (14.5 mM [sic]) of 2-(2-chloroethyl)-3,3-dimethyl-2,3-dihydro-1,2-benzoisothiazole 1,1-dioxide and 2.0 g(14.5 mM [sic]) of finely powdered potassium carbonate were added to 3.0g (14.5 mM [sic]) of (+)-(1S,5R,6S)-exo-6-(4-chlorophenyl)-3-azabicyclo-[3.2.0]heptane in 60 ml ofxylene, and the mixture was refluxed for 7 h. It was then concentratedin a rotary evaporator, and the residue was partitioned in water andmethylene chloride at pH 10. The aqueous phase was extracted once morewith methylene chloride, and then the combined organic phases wereconcentrated. The crude product was purified by column chromatography(silica gel, mobile phase methylene chloride/methanol 98/2. 4.2 g (69%)of product were isolated as an oil, which was dissolved in 200 ml ofether and converted with ethereal HCl into the hydrochloride (m.p. 230to 232° C.). [α]_(D)=+60.9° (EtOH)

Elemental analysis C₂₃H₂₇N₂O₂SCl×HCl; Calculated C, 59.10 H, 6.04 N,5.99; Found C, 59.3 H, 6.3 N, 5.7.

EXAMPLE 2(+)-(1S,5R,6S)-Exo-2-[2-[6-(4-chlorophenyl)-3-azabicyclo-[3.2.0]heptan-3-yl]ethyl]-2,3-dihydro-1,2-benzoisothiazole 1,1-dioxide×HCl

360 mg (12.0 mM [sic]) of 80% sodium hydride were added to 2.0 g (11.8mM [sic]) of 2,3-dihydro-1,2-benzoisothiazole 1,1-dioxide in 30 ml ofDMF, and the mixture was stirred at a bath temperature of 90 to 100° C.for 2 h. After cooling, 3.2 g (11.8 mM [sic]) of(+)-(1S,5R,6S)-exo-[3-(2-chloro)ethyl]-6-(4-chlorophenyl)-3-azabicyclo[3.2.0]heptane were added, and the mixture was stirred at a bathtemperature of 100° C. for 2 h. After cooling, the mixture waspartitioned between methyl tert-butyl ether and water at pH 10, and theaqueous phase was extracted once more with methyl tert-butyl ether. Theorganic phases were combined and concentrated. The crude product waspurified by column chromatography (silica gel, mobile phase methylenechloride/methanol 98/2). 4.5 g (95%) of product were isolated as an oil([α]_(D)=+69.9°; EtOH) which was dissolved in 200 ml of ether andconverted with ethereal HCl into the hydrochloride (m.p. 240 to 242°C.).

Elemental analysis C₂₁H₂₃N₂O₂SCl×HCl; Calculated C, 57.40 H, 5.51 N,6.38 Cl 16.14; Found C, 57.1 H, 5.5 N, 6.2 Cl 16.0.

The following were prepared in analogy to Example 1 and 2:

3.(+)-(1S,5R,6S)-Exo-2-[2-[6-4-fluorophenyl)-3-azabicyclo-[3.2.0]heptan-3-yl]ethyl]-3,3-dimethyl-2,3-dihydro-1,2-ben-zoisothiazole 1,1-dioxide, m.p.113 to 115° C.

4.(+)-(1S,5R,6S)-Exo-2-[2-[6-(4-fluorophenyl)-3-azabicyclo-[3.2.0]heptan-3-yl]ethyl]-3,3-diethyl-2,3-dihydro-1,2-benzoisothiazole1,1-dioxide×HCl×H₂O, m.p. 77 to 79° C.

5.(+)-(1S,5R,6S)-Exo-2-[2-[6-(4-fluorophenyl)-3-azabicyclo-[3.2.0]heptan-3-yl]ethyl]-2,3-dihydro-1,2-benzoisothiazole1,1-dioxide×HCl, m.p. 234 to 236° C., [α]_(D)=+67.1° (EtOH)

6.(+)-(1S,5R,6S)-Exo-2-[2-[6-(4-chlorophenyl)-3-azabicyclo-[3.2.0]heptan-3-yl3-ethyl]-3,3-dimethyl-4-chloro-2,3-dihydro-1,2-benzisothiazole-1,1-dioxide×HCl, m.p. 225 to 227° C.

We claim:
 1. An N-substituted 3-azabicyclo[3.2.0]heptane derivative ofthe formula I:

in which R¹ is fluorine or chlorine, R² and R³ are hydrogen orC₁-C₃-alkyl, and R⁴ is chlorine, methyl, nitro or amino, and the saltsthereof with physiologically tolerated acids.
 2. A method for treating aneuroleptic disease which comprises administering to a host in needthereof a neuroleptically effective amount of a compound as defined inclaim 1.